The present invention relates to anti-inflammatory compositions. More particularly, the present invention relates to an anti-inflammatory composition comprising GM2 activator protein.
Inflammation is generally a protective response triggered by tissue injury or destruction. It is characterized physically by pain, heat, redness, swelling and loss of function, and histologically by a complex series of events which include dilatation of arterioles, leakage in capillaries and venules, exudation of plasma and other fluids, and migration of leukocytes into the inflammatory focus. Although characterized as a protective response, disorders exist in which prolonged or chronic inflammation is undesirable because it causes extreme discomfort as well as extensive tissue damage. Examples of such inflammatory disorders include auto-immune disease, hypersensitivity, rheumatism (such as rheumatoid arthritis), vasculitis, asthma, allergies, rhinitis, gout and tissue-specific conditions such as glomerulonephritis and hepatitis.
Many xe2x80x9canti-inflammatoryxe2x80x9d drugs exist today which are used to treat the symptoms associated with inflammatory disorders. Treatments including both steroidal and non-steroidal (NSAIDS) drugs are known. Unfortunately, undesirable side effects are commonly encountered with the use of either of these treatments. NSAIDS, such as the salicylates and related compounds, for example, exhibit toxicity, and can cause gastric and intestinal ulceration, disturbances in platelet function and changes in renal function. Steroidal treatments also exhibit toxicity, and have been found to adversely effect infant growth, development and immune response, and cause bone fragility in older patients.
There exists a need, thus, to develop compounds useful to treat inflammation which are non-toxic, present with less severe side effects and which are more efficacious than existing therapies. In this regard, it would be highly desirable to develop an anti-inflammatory derived from a naturally-occurring compound native to the mammalian system.
During the past two decades, studies describing the chemistry and biology of PAF (platelet activating factor) have been extensive. This potent phosphoacylglycerol exhibits a wide variety of physiological and pathophysiological effects in various cells and tissues. PAF acts, through specific receptors and a variety of signal transduction systems, to elicit diverse biochemical responses (Chao and Olson, Biochemical Journal, 292:617-29, 1993). The role of PAF in the inflammatory response is particularly important. It is believed to promote adhesion of polymorphonuclear leukocytes (PMNs) to the endothelium at a site of inflammation and subsequent migration of PMNs through the endothelial barrier, both of which are crucial steps in an inflammatory response.
PAF, along with cytokines such as the interleukins, tumor necrosis factor and others, appear to be involved in the inflammation that is associated with inflammatory bowel diseases such as Crohn""s disease, ulcerative colitis, ischemic colitis, or antibiotic-associated colitis (Kubes, Canadian Journal of Physiology and Pharmacology, 71:88-97, 1993). PAF is also one of the chemical mediators that may participate in the inflammatory process underlying asthma.
Inhibitors of PAF have been developed as potential therapeutics for the treatment and management of such inflammatory diseases. However, most PAF inhibitors are directed at receptors of PAF rather than PAF itself (Chao and Olson,supra; Izumi and Shimizu, Biochimica et Biophysica Acta, 1259:317-33,1995). Such inhibitors have been found to lack efficacy due to receptor-heterogeneity and, thus, inhibit only a subset of PAF receptors.
The GM2 activator protein, a substrate specific cofactor for the enzyme, lysosomal beta-hexosaminidase A (Hex A), which catalyzes the hydrolysis of GM2 ganglioside (GM2), has now been found to inhibit PAF by directly binding thereto.
Accordingly, in one aspect of the present invention, there is provided an anti-inflammatory composition comprising GM2 activator protein, or a GM2 activator peptide derived therefrom, in combination with at least one pharmaceutically acceptable carrier.
In another aspect of the present invention there is provided a method of treating an inflammatory condition in a mammal comprising administering to said mammal a therapeutically effective amount of a composition comprising GM2 activator protein, or a GM2 activator peptide derived therefrom, and at least one pharmaceutically acceptable carrier.
In a further aspect of the present invention, an article of manufacture is provided comprising packaging material and a pharmaceutical composition contained within said packaging material, wherein said pharmaceutical composition is therapeutically effective to reduce inflammation in the body of a mammal, and wherein the packaging material comprises a label which indicates that the composition can be used to reduce inflammation, said composition comprising GM2 activator protein, or a GM2 activator peptide derived therefrom, and at least one pharmaceutically acceptable carrier.
Embodiments of the present invention are described in greater detail with reference to the accompanying drawings in which: